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Neuroinflammation in Alzheimer’s Disease: Current Progress in Molecular Signaling and Therapeutics

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Alzheimer’s disease, a neurodegenerative disease with amyloid beta accumulation as a major hallmark, has become a dire global health concern as there is a lack of clear understanding of the causative agent. It is a major cause of dementia which is increasing exponentially with age. Alzheimer’s disease is marked by tau hyperphosphorylation and amyloid beta accumulation that robs people of their memories. Amyloid beta deposition initiated a spectrum of microglia-activated neuroinflammation, and microglia and astrocyte activation elicited expressions of various inflammatory and anti-inflammatory cytokines. Neuroinflammation is one of the cardinal features of Alzheimer’s disease. Pro-inflammatory cytokine signaling plays multifarious roles in neurodegeneration and neuroprotection. Induction of proinflammatory signaling leads to discharge of immune mediators which affect functions of neurons and cause cell death. Sluggish anti-inflammatory system also contributes to neuroinflammation. Numerous pathways like NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide, and COX are involved in triggering brain immune cells like astrocytes and microglia to secrete inflammatory cytokines such as tumor necrosis factor, interleukins, and chemokines and participate in Alzheimer’s disease pathology. PPAR-γ agonists tend to boost the phagocytosis of amyloid beta and decrease the inflammatory cytokine IL-1β. Recent findings suggest the cross-link between gut microbiota and neuroinflammation contributing in AD which has been explained in this study. The role of cellular, molecular pathways and involvement of inflammatory mediators in neuroinflammation has also been described; targeting them could be a potential therapeutic strategy for treatment of AD.

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  1. Sahab Uddin, Md, Abdullah Al Mamun, Md Tanvir Kabir, & Ghulam, Md Ashraf, May N Bin-Jumah, and Mohamed M Abdel-Daim. Multi-target drug candidates for multifactorial Alzheimer’s disease: AChE and NMDAR as molecular targets.

  2. Shal, Bushra, Wei Ding, Hussain Ali, Yeong S. Kim, and Salman Khan. 2018. Anti-neuroinflammatory potential of natural products in attenuation of Alzheimer’s disease. Frontiers in Pharmacology 9. Frontiers Media S.A.: 548.

  3. Jonkman, Laura E., Martijn D. Steenwijk, Nicky Boesen, Annemieke J.M. Rozemuller, Frederik Barkhof, Jeroen J.G. Geurts, Linda Douw, and Wilma D.J. van de Berg. 2020. Relationship between β-amyloid and structural network topology in decedents without dementia. Neurology 95. American Academy of Neurology: e532.

  4. Pathak, Yashwant. Genomics-Driven Healthcare.

  5. Zheng, Cong, Xin Wen Zhou, and Jian Zhi Wang. 2016. The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-α, TGF-β and IFN-γ. Translational Neurodegeneration 2016 5:1 5. BioMed Central: 1–15.

  6. Gauthier, Serge, P. S. Aisen, J. Cummings, M. J. Detke, F. M. Longo, R. Raman, M. Sabbagh, et al. 2020. Non-amyloid approaches to disease modification for Alzheimer’s disease: an EU/US CTAD task force report. The Journal of Prevention of Alzheimer’s Disease 2020 7:3 7. Springer: 152–157.

  7. Sinyor, Benjamin, Jocelyn Mineo, and Christopher Ochner. 2020. Alzheimer’s disease, inflammation, and the role of antioxidants. Journal of Alzheimer’s Disease Reports 4. IOS Press: 175–183.

  8. Dionisio-Santos, Dawling A., John A. Olschowka, and M. Kerry O’Banion. 2019. Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer’s disease. Journal of Neuroinflammation 2019 16:1 16. BioMed Central: 1–13.

  9. DiSabato, Damon J., Ning Quan, and Jonathan P. Godbout. 2016. Neuroinflammation: the devil is in the details. Journal of neurochemistry 139. NIH Public Access: 136.

  10. Norden, Diana M., Paige J. Trojanowski, Emmanuel Villanueva, Elisa Navarro, and Jonathan P. Godbout. 2016. Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge. Glia 64. NIH Public Access: 300.

  11. Kinney, Jefferson W., Shane M. Bemiller, Andrew S. Murtishaw, Amanda M. Leisgang, Arnold M. Salazar, and Bruce T. Lamb. 2018. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s & Dementia : Translational Research & Clinical Interventions 4. Wiley-Blackwell: 575.

  12. Saito, Takashi, and Takaomi C. Saido. 2018. Neuroinflammation in mouse models of Alzheimer’s disease. Clinical and Experimental Neuroimmunology 9. John Wiley & Sons, Ltd: 211–218.

  13. Figueiredo-Pereira, Maria E., Patricia Rockwell, Thomas Schmidt-Glenewinkel, and Peter Serrano. 2015. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration. Frontiers in Molecular Neuroscience 7. Frontiers Media S.A.: 1–20.

  14. Taipa, Ricardo, P. Sofia, das Neves, Ana L. Sousa, Joana Fernandes, Claudia Pinto, Ana P. Correia, Ernestina Santos, et al. 2019. Proinflammatory and anti-inflammatory cytokines in the CSF of patients with Alzheimer’s disease and their correlation with cognitive decline. Neurobiology of Aging 76: 125–132.

    Article  CAS  PubMed  Google Scholar 

  15. Heneka, Michael T., Monica J. Carson, Joseph El Khoury, Gary E. Landreth, Frederic Brosseron, Douglas L. Feinstein, Andreas H. Jacobs, et al. 2015. Neuroinflammation in Alzheimer’s disease. The Lancet Neurology. Lancet Publishing Group.

  16. Leng, Fangda, and Paul Edison. 2021. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nature Reviews Neurology. Vol. 17.

  17. Yang, Seung Hoon. 2019. Cellular and molecular mediators of neuroinflammation in Alzheimer disease. International Neurourology Journal 23. Korean Continence Society: S54.

  18. Li, Si tong, Qi Dai, Shu xian Zhang, Ya jun Liu, Qiu qiong Yu, Fei Tan, Shu hong Lu, et al. 2018. Ulinastatin attenuates LPS-induceds inflammation in mouse macrophage RAW264.7 cells by inhibiting the JNK/NF-κB signaling pathway and activating the PI3K/Akt/Nrf2 pathway. Acta Pharmacologica Sinica 2018 39:8 39. Nature Publishing Group: 1294–1304.

  19. Hemonnot, Anne Laure, Jennifer Hua, Lauriane Ulmann, and Hélène Hirbec. 2019. Microglia in Alzheimer disease: well-known targets and new opportunities. Frontiers in Aging Neuroscience 11. Frontiers Media SA.

  20. Liu, Ting, Lingyun Zhang, Donghyun Joo, and Shao Cong Sun. 2017. NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy 2017 2:1 2. Nature Publishing Group: 1–9.

  21. Liu et al. - 2017 - NF-κB signaling in inflammation - Signal Transduction and Targeted Therapy.pdf.

  22. Jha, Niraj Kumar, Saurabh Kumar Jha, Rohan Kar, Parma Nand, Kumari Swati, and Vineet Kumar Goswami. 2019. Nuclear factor-kappa β as a therapeutic target for Alzheimer’s disease. Journal of Neurochemistry 150: 113–137.

    Article  CAS  PubMed  Google Scholar 

  23. Messemer, Nanette, Christin Kunert, Marcus Grohmann, Helga Sobottka, Karen Nieber, Herbert Zimmermann, Heike Franke, et al. 2013. P2X7 receptors at adult neural progenitor cells of the mouse subventricular zone. Neuropharmacology 73. Neuropharmacology: 122–137.

  24. Choi, Hyun B., Jae K. Ryu, Seung U. Kim, and James G. McLarnon. 2007. Modulation of the purinergic P2X7 receptor attenuates lipopolysaccharide-mediated microglial activation and neuronal damage in inflamed brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 27. J Neurosci: 4957–4968.

  25. Behl, Tapan, Bijo Mathew, Asma Perveen, George E Barreto, May N Bin-jumah, and Mohamed M Abdel-daim. 2020. 1 INTRODUCTION 2 BRIEF OUTLINE Of mTOR SIGNALING PATHWAY 72: 1843–1855.

  26. Mueed, Zeba, Pallavi Tandon, Sanjeev Kumar Maurya, Ravi Deval, Mohammad A. Kamal, and Nitesh Kumar Poddar. 2019. Tau and mTOR: the hotspots for multifarious diseases in Alzheimer’s development. Frontiers in Neuroscience 13. Frontiers Media S.A.: 1017.

  27. Uddin, Md Sahab, Md Ataur Rahman, Md Tanvir Kabir, Tapan Behl, Bijo Mathew, Asma Perveen, George E. Barreto, May N. Bin-Jumah, Mohamed M. Abdel-Daim, and Ghulam Md Ashraf. 2020. Multifarious roles of mTOR signaling in cognitive aging and cerebrovascular dysfunction of Alzheimer’s disease. IUBMB Life 72. John Wiley & Sons, Ltd: 1843–1855.

  28. Kheiri, Ghazaleh, Mahsa Dolatshahi, Farzaneh Rahmani, and Nima Rezaei. 2019. Role of p38/MAPKs in Alzheimer’s disease: Implications for amyloid beta toxicity targeted therapy. Reviews in the Neurosciences 30. De Gruyter: 9–30.

  29. Lee, Jong Kil, and Nam Jung Kim. 2017. Recent advances in the inhibition of p38 MAPK as a potential strategy for the treatment of Alzheimer’s disease. Molecules 2017, Vol. 22, Page 1287 22. Multidisciplinary Digital Publishing Institute: 1287.

  30. Dinarello, Charles A. 2000. Proinflammatory cytokines. Chest 118. Chest: 503–508.

  31. Wang, Wen Ying, Meng Shan Tan, Yu. Jin Tai, and Lan Tan. 2015. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Annals of Translational Medicine 3: 1–17.

    Article  CAS  Google Scholar 

  32. Mrak, Robert E., and W.S.T. Griffin. 2000. Interleukin-1 and the immunogenetics of Alzheimer disease. Journal of Neuropathology and Experimental Neurology 59: 471–476.

    Article  CAS  PubMed  Google Scholar 

  33. Williamson, Lauren L., Paige W. Sholar, Rishi S. Mistry, Susan H. Smith, and Staci D. Bilbo. 2011. Microglia and memory: Modulation by early-life infection. Journal of Neuroscience 31: 15511–15521.

    Article  CAS  PubMed  Google Scholar 

  34. Alves, Sandro, Guillaume Churlaud, Mickael Audrain, Kristin Michaelsen-Preusse, Romain Fol, Benoit Souchet, Jérôme. Braudeau, Martin Korte, David Klatzmann, and Nathalie Cartier. 2017. Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer’s disease mice. Brain 140: 826–842.

    Article  PubMed  Google Scholar 

  35. Lyra e Silva, Natalia M., Rafaella A. Gonçalves, Tharick A. Pascoal, Ricardo A.S. Lima-Filho, Elisa de Paula França Resende, Erica L.M. Vieira, Antonio L. Teixeira, et al. 2021. Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer’s disease. Translational Psychiatry 11. Springer US.

  36. Su, Fan, Feng Bai, and Zhijun Zhang. 2016. Inflammatory cytokines and Alzheimer’s disease: a review from the perspective of genetic polymorphisms. Neuroscience Bulletin 32. Springer: 469.

  37. Chang, Rudy, Jillian Knox, Jae Chang, Aram Derbedrossian, Vitaly Vasilevko, David Cribbs, Ruben J. Boado, William M. Pardridge, and Rachita K. Sumbria. 2017. Blood-brain barrier penetrating biologic TNF-α inhibitor for Alzheimer’s disease. Molecular Pharmaceutics 14: 2340–2349.

    Article  CAS  PubMed  Google Scholar 

  38. Ekert, Justyna O., Rebecca L. Gould, Gemma Reynolds, and Robert J. Howard. 2018. TNF alpha inhibitors in Alzheimer’s disease: a systematic review. International Journal of Geriatric Psychiatry 33. John Wiley & Sons, Ltd: 688–694.

  39. McGeer, Patrick L., and Edith G. McGeer. 2001. Polymorphisms in inflammatory genes and the risk of Alzheimer disease. Archives of Neurology 58. American Medical Association: 1790–1792.

  40. Zhang, Yonggang, Jie Zhang, Can Tian, Yuling Xiao, Xiaobo Li, Chao He, Jin Huang, and Hong Fan. 2011. The -1082G/A polymorphism in IL-10 gene is associated with risk of Alzheimer’s disease: A meta-analysis. Journal of the Neurological Sciences 303: 133–138.

    Article  CAS  PubMed  Google Scholar 

  41. Porro, Chiara, Antonia Cianciulli, and Maria Antonietta Panaro. 2020. The regulatory role of IL-10 in neurodegenerative diseases. Biomolecules 10. Multidisciplinary Digital Publishing Institute (MDPI): 1–15.

  42. Rubio-Perez, Jose Miguel, and Juana Maria Morillas-Ruiz. 2012. A review: inflammatory process in Alzheimer’s disease, role of cytokines. The Scientific World Journal 2012. Hindawi Limited.

  43. Shen, Heping, Qiaobing Guan, Xiaoling Zhang, Chao Yuan, Zhengye Tan, Liping Zhai, Yanan Hao, Yanling Gu, and Chenyang Han. 2020. New mechanism of neuroinflammation in Alzheimer’s disease: the activation of NLRP3 inflammasome mediated by gut microbiota. Progress in Neuro-Psychopharmacology and Biological Psychiatry 100. Elsevier Inc.: 109884.

  44. Lin, Li, Li Juan Zheng, and Long Jiang Zhang. 2018. Neuroinflammation, gut microbiome, and Alzheimer’s disease. Molecular Neurobiology 55. Humana Press Inc.: 8243–8250.

  45. Goyal, Divya, Syed Afroz Ali, and Rakesh Kumar Singh. 2021. Emerging role of gut microbiota in modulation of neuroinflammation and neurodegeneration with emphasis on Alzheimer’s disease. Progress in Neuro-Psychopharmacology and Biological Psychiatry 106. Elsevier Inc.: 110112.

  46. Megur, Ashwinipriyadarshini, Daiva Baltriukienė, Virginija Bukelskienė, and Aurelijus Burokas. 2020. The microbiota–gut–brain axis and Alzheimer’s disease: neuroinflammation is to blame? Nutrients 2021, Vol. 13, Page 37 13. Multidisciplinary Digital Publishing Institute: 37.

  47. Lin, Caixiu, Shuai Zhao, Yueli Zhu, Ziqi Fan, Jing Wang, Baorong Zhang, and Yanxing Chen. 2019. Microbiota-gut-brain axis and toll-like receptors in Alzheimer’s disease. Computational and Structural Biotechnology Journal 17. Elsevier: 1309–1317.

  48. Thouennon, Erwan, Yong Cheng, Vida Falahatian, Niamh X. Cawley, and Yoke Peng Loh. 2015. Rosiglitazone-activated PPARγ induces neurotrophic factor-α1 transcription contributing to neuroprotection. Journal of Neurochemistry 134: 463–470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gottschalk, William Kirby. 2021. in Neuroscience Reassessment of Pioglitazone for Alzheimer ’ s Disease: 1–76.

  50. Xiao, Shifu, Piu Chan, Tao Wang, Zhen Hong, Shuzhen Wang, Weihong Kuang, Jincai He, et al. 2021. A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s dementia. Alzheimer’s research & therapy 13. Alzheimers Res Ther.

  51. Liu, Ming, Qin Nie, Xianliang Xin, and Meiyu Geng. 2008. Identification of AOSC-binding proteins in neurons. Chinese Journal of Oceanology and Limnology 26: 394–399.

    Article  CAS  Google Scholar 

  52. Sun, Weiying, Jun Zhao, and Chunzhi Li. 2020. Dexmedetomidine provides protection against hippocampal neuron apoptosis and cognitive impairment in mice with Alzheimer’s Disease by mediating the miR-129/YAP1/JAG1 axis. Molecular neurobiology 57. Mol Neurobiol: 5044–5055.

  53. Zhao, Yang, Jianshuai He, Ning Yu, Changxin Jia, and Shilei Wang. 2020. Mechanisms of dexmedetomidine in neuropathic pain. Frontiers in Neuroscience 14. Frontiers Media S.A.: 330.

  54. Howard, Robert, Olga Zubko, Rosie Bradley, Emma Harper, Lynn Pank, John O Brien, Chris Fox, et al. 2020. Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease a randomized clinical trial 77: 164–174.

  55. Therapeutics, Search, Therapeutics Home, Montelukast Synonyms, Chemical Name, Therapy Type, Small Molecule, Target Type, Disease U S F D A Status, Intelgenx Approved, and Aldea Perona. 2016. THERAPEUTICS Montelukast: 1–5.

  56. Zhou, Mengshi, Xu. Rong, David C. Kaelber, and Mark E. Gurney. 2020. Tumor necrosis factor (TNF) blocking agents are associated with lower risk for Alzheimer’s disease in patients with rheumatoid arthritis and psoriasis. PLoS ONE 15: 1–14.

    Article  CAS  Google Scholar 

  57. Tufan, Ayse N., and Fatih Tufan. 2015. Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. Neurology 85: 2083–2084.

    Article  PubMed  Google Scholar 

  58. Yang, Lijuan, Yepei Liu, Yuanyuan Wang, Junsheng Li, and Na. Liu. 2021. Azeliragon ameliorates Alzheimer’s disease via the janus tyrosine kinase and signal transducer and activator of transcription signaling pathway. Clinics 76: 1–8.

    Article  Google Scholar 

  59. Ettcheto, Miren, Amanda Cano, Elena Sanchez-López, Ester Verdaguer, Jaume Folch, Carme Auladell, and Antoni Camins. 2021. Masitinib for the treatment of Alzheimer’s disease. Neurodegenerative Disease Management 11: 263–276.

    Article  PubMed  Google Scholar 

  60. Pharmaceuticals, Biohaven. COVID-19 Information Try the modernized ClinicalTrials . gov beta website . Learn more about the modernization effort . Trial record 1 of 1 for : Study of BHV-4157 in Alzheimer ’ s Disease ( T2 Protect AD ): 1–7.

  61. Sestito, Simona, Simona Daniele, Deborah Pietrobono, Valentina Citi, Lorenza Bellusci, Grazia Chiellini, Vincenzo Calderone, Claudia Martini, and Simona Rapposelli. 2019. Memantine prodrug as a new agent for Alzheimer’s disease. Scientific Reports 9: 1–11.

    Article  CAS  Google Scholar 

  62. Mogi, Masaki, Jian Mei Li, Kana Tsukuda, Jun Iwanami, Li Juan Min, Akiko Sakata, Teppei Fujita, Masaru Iwai, and Masatsugu Horiuchi. 2008. Telmisartan prevented cognitive decline partly due to PPAR-γ activation. Biochemical and Biophysical Research Communications 375: 446–449.

    Article  CAS  PubMed  Google Scholar 

  63. Karkhah, Ahmad, Mahdiye Saadi, Fereshteh Pourabdolhossein, Kiarash Saleki, and Hamid Reza Nouri. 2021. Indomethacin attenuates neuroinflammation and memory impairment in an STZ-induced model of Alzheimer’s like disease. 43. Taylor & Francis: 758–766.

  64. Rivers-Auty, Jack, and Alzheimer’s Disease Neuroimaging Initiative, Alison E Mather, Alzheimer’s Disease Neuroimaging Initiative, Ruth Peters, Alzheimer’s Disease Neuroimaging Initiative, Catherine B Lawrence, Alzheimer’s disease neuroimaging initiative, David Brough, and Alzheimer’s disease neuroimaging initiative. 2020. Anti-inflammatories in Alzheimer’s disease—potential therapy or spurious correlate? Brain Communications 2. Oxford Academic.

    Article  Google Scholar 

  65. Prins, Niels D., John E. Harrison, Hui May Chu, Kelly Blackburn, John J. Alam, Philip Scheltens, Arnold, et al. 2021. A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer’s disease. Alzheimer’s Research and Therapy 13. BioMed Central Ltd: 1–12.

  66. Wang, Xinyi, Guangqiang Sun, Teng Feng, Jing Zhang, Xun Huang, Tao Wang, Zuoquan Xie, et al. 2019. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Research 2019 29:10 29. Nature Publishing Group: 787–803.

  67. Plascencia-Villa, Germán, and George Perry. 2020. Status and future directions of clinical trials in Alzheimer’s disease. International Review of Neurobiology 154. Academic Press: 3–50.

  68. Guo, Libing, Jiaxin Xu, Yunhua Du, Weibo Wu, Wenjing Nie, Dongliang Zhang, Yuling Luo, et al. 2021. Effects of gut microbiota and probiotics on Alzheimer’s disease. Translational Neuroscience 12. De Gruyter Open Ltd: 573–580.

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Sujata Thakur wrote the manuscript, Rishika Dhapola wrote the manuscript, Phulen Sarma wrote the manuscript, Bikash Medhi designed and edited the manuscript, and Dibbanti HariKrishna Reddy designed, wrote, and edited the manuscript.

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Correspondence to Dibbanti HariKrishna Reddy.

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Thakur, S., Dhapola, R., Sarma, P. et al. Neuroinflammation in Alzheimer’s Disease: Current Progress in Molecular Signaling and Therapeutics. Inflammation 46, 1–17 (2023).

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